ABSTRACT Support from this grant led to our prior successful discovery and development of the triterpene bevirimat, which is currently in Phase IIb clinical trials. Encouraged by this success, the objectives of the proposed research remain to continuously discover and develop novel anti-HIV clinical trials candidates (other than bevirimat) from plant-derived natural products and their analogs. The following specific studies will be carried out to accomplish our objectives: 1. To discover new leads from natural products. We will identify potent anti-HIV principles from extracts of more than 60 previously unexplored plant species 2. To optimize already identified leads (different from bevirimat). We will focus on synthesizing new water-soluble DCP (chromone) and gomisin G (lignan) analogs, with a goal of enhancing biological profiles, such as overcoming cross-resistance and increasing potency. These two compound classes are chosen for further development, because they are nanomolar HIV-1 inhibitors with unique structures and novel mechanisms of action. 3. To further determine anti-HIV-1 activity and mechanism of action for new and promising candidates. We will conduct both HIV drug screening and mechanistic assays, respectively. The main objectives are to identify novel compounds with potent anti-HIV-1 activity and novel mechanisms of action, including families of compounds with activity against HIV isolates resistant to currently approved drugs. Our strategies are expected to identify the drug targets as well as compounds with novel mechanism of action. A distinctive and valuable collaboration between two academic institutions [Dr. K.H. Lee, Natural Products Research Laboratories (NPRL), UNC and Dr. C.H. Chen, Duke University] has been established and is ongoing to discover and develop novel small molecule HIV inhibitors from natural products and their synthetic analogs. The NPRL has expertise in the bioactivity-directed fractionation and isolation (BDFI) and characterization of bioactive natural products coupled with structural modification of the new leads to optimize their pharmaceutical profiles. Dr. Chen's laboratory at Duke University has the needed expertise, experience, and resources to perform initial activity screening, as well as further mechanistic and pharmacological studies to develop the natural product-based inhibitors through preclinical studies. The long term goal is to identify potent HIV inhibitors with novel structures and mechanisms of action to augment the arsenal of approved HIV drugs. The development of the most promising new leads for clinical trials will be accomplished through licensing the technology to a pharmaceutical company, like Panacos Pharmaceuticals or others, as we did before for the development of bevirimat into clinical trials.